Proteins such as cytokines produced by T helper 1 (Th1) and T helper 2 cells (Th2) cells are thought to play critical roles in autoimmune and inflammatory diseases and it is thought that these diseases can be treated using methods to alter the activities of these proteins. Consequently, genes that are expressed in (Th1) and (Th2) cells are of interest.
Naïve CD4+ T cells can differentiate to Th1 and Th2 cells. Th1 cells are characterized for their production of IFN-γ but not IL-4 while Th2 cells produce IL-4 but not IFN-γ. IFN-γ and IL-4 are two major cytokines involved in autoimmunity and inflammation. After the engagement of TCR-peptide-MHC class II complex, naïve CD4+ T cells expend and develop to Th1 cells when IL-12 but not IL-4 is present; cells develop to Th2 cells when the environment has IL-4 but not IL-12.
CD4+ Th1 play critical roles in cell-mediated immune response while Th2 cells are involve in humoral immunity. However, over activation of CD4+ Th1 and Th2 cells may induce autoimmune and inflammatory diseases. For example, Th2, and also Th1, responses are involved in asthma. Th1 or Th2 responses might be the cause of different type of IBD and myocarditis. Type I diabetes and arthritis may be caused by Th1 response. In order to inhibit the Th1 or Th2 response, it is necessary to discover Th1 or Th2-specific genes which may be involved in their proliferation, differentiation and/or or cytokine production.
The cytokines and surface molecules of Th1/Th2 are involved in the autoimmune and inflammatory diseases. IFNγ, TNFα and IL-2 are mainly produced by Th1 cells, while IL-4, IL-5 and IL-13 are mainly produced by Th2 cells. IFNγ, TNFα and IL-2 all play important roles in the Th1-mediated diseases, such as IBD, MS, EAE, diabetes and arthritis. IL-4 is thought to play a role in asthma. Meanwhile, B7s and B7 receptors play critical roles in the stimulation or inhibition of T cell activation. B7.1 (CD80) and B7.2 (CD86) expressed on antigen presenting cells could stimulate either CD28 or CTLA-4 (CD152) expressed on T cells. Once B7-CD28 ligation occurs, T cells receive positive signals and the cells will be activated with the combination of TCR signals. However, when B7 stimulates CTLA-4, the T cell activation will be inhibited by the CTLA-4 signal. Programmed death receptor 1 (PD-1) is another inhibitory surface molecule. PD-1 deficient mice developed autoimmunity. Finally, a new inhibitory receptor called B and T lymphocyte attenuator (BTLA), initially discovered by Jianfei Yang and Ken Murphy, was recently published in Nature Immunology (2003) 4: 670-679. Increased EAE susceptibility in BTLA-deficient mice was found.